Since the discovery of norfloxacin, synthetic quinolone antibacterial agents have been improved in antibacterial activity and pharmacokinetics, and many compounds are now used in the clinical filed as chemotherapeutic agents which are effective for in almost systemic infectious diseases.
In recent years, generation of bacteria having low sensitivity to synthetic quinolone antibacterial agents have been increasing in clinical situations. For example, like the case of Staphylococcus aureus (MRSA) and Streptococcus pneumococcus (PRSP) which are insusceptible to β-lactam antibiotics and Enterococcus (VRE) which is insusceptible to aminoglycoside antibacterial agents, a case has been increasing in which a gram-positive bacteria originally resistant to drugs other than synthetic quinolone antibacterial agents also became low sensitive to synthetic quinolone antibacterial agents. In consequence, synthetic quinolone antibacterial agents having higher efficacy are thus being demanded in clinical situations.
With regard to the side effects of synthetic quinolone antibacterial agents, in addition to the central nervous system stimulation effect, which has been a problem since priorly, the induction of convulsion resulting from combined use with nonsteroidal anti-inflammatory agents, phototoxicity, etc. have also become known, and the development of synthetic quinolone antibacterial agents having higher safety is thus also being demanded.
It is known that the structure of the substituents at the 7-position and 1-position (or positions corresponding to these positions; the same shall apply hereinafter) have a large influence on the antibacterial activity, pharmacokinetics, and safety of synthetic quinolone antibacterial agents.
Quinolone derivatives, having a pyrrolidinyl group having an aminomethyl group at the 3-position, as the substituent at the 7-position of the quinolone mother skeleton, are known to exhibit strong antibacterial activity against gram-negative and gram-positive bacteria. For example, there are 7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives [Journal of Medicinal Chemistry, vol. 29, p. 445 (1986)].
Furthermore, known examples of quinolone carboxylic acid derivatives having a substituent on the carbon atom of the aminomethyl group of the 3-(1-aminomethyl)pyrrolidin-1-yl group include 7-[3-(1-aminoethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives [Journal of Medicinal Chemistry, vol. 36, p. 871 (1993)]; 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives [Journal of Medicinal Chemistry, vol. 37, p. 733 (1994)]; and 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolone carboxylic acid derivatives [Chemical and Pharmaceutical Bulletin, vol. 42, p. 1442 (1994)], etc.
However, though the abovementioned quinolone derivatives, having a 3-(aminomethyl)pyrrolidin-1-yl group, a 3-(1-aminoethyl)pyrrolidin-1-yl group, or a group having a structure similar to these as a substituent, are compounds which exhibit strong antibacterial activity, it has been found that due to the low selective toxicity [see for example, Journal of Antimicrobial Chemotherapy, vol. 33, p. 685 (1994)], these compounds act not only on bacteria but also on the cells of eukaryotic organisms, and they are difficult to use as medical drugs or as veterinary drugs. Therefore, quinolone compounds having these substituents have not been put to actual clinical use up until now.
Meanwhile, quinolone carboxylic acid derivatives, which have a 3-(1-aminocycloalkyl)pyrrolidin-1-yl group as a substituent and are relevant to the present invention, have been described in the form of a broad concept in PCT/JP96/00208, which provides a description of compounds with the structure shown in formula A or formula B. That is, with a quinolone compound of formula A, the substituent (X1) at the 6-position is defined as being a halogen atom or a hydrogen atom. However, only quinolone carboxylic acids wherein the fluorine atom or other halogen atom is the substituent at the 6-position are disclosed specifically in the abovementioned patent application. Therefore, PCT/JP96/00208 does not provide a specific description concerning quinolone carboxylic acids wherein hydrogen is substituted at the 6-position. Furthermore, this publication does not provide any specific disclosure as embodiments of 3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolone carboxylic acids, wherein the present invention is concerned.

[In the above formula A, X1 represents a halogen atom or a hydrogen atom and X2 represents a halogen atom. (The definitions of the substituents in the compound shown in formula A are those given in PCT/JP96/00208 and are irrelevant to the definitions of substituents of the present invention even when the same symbols are used.)]
In the above formula A, R2 is represented by formula B:

[In the above formula B, p represents an integer from 1 to 3, q represents an integer from 1 to 3, R9 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R10 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms that has a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms that has a halogen atom. (The definitions of the substituents in the compound shown in formula B are those given in PCT/JP96/00208 and are irrelevant to the definitions of substituents of the present invention even when the same symbols are used.)]
Besides the above, an example of a literature that indicates a quinolone carboxylic acid derivative, which has a 3-(1-aminocycloalkyl) pyrrolidin-1-yl group and is relevant to the present invention, is Chemical and Pharmaceutical Bulletin, vol. 42, p. 1442 (1994). However, this literature does not contain any description whatsoever concerning 3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolone carboxylic acids, which are compounds of the present invention.
Furthermore, for example, PCT/WO99/14214 indicates a 6-hydrogen-substituted-quinolone carboxylic acid derivative, in which a nitrogen-containing heterocyclic substituent, for example, the 3-(1-aminoethyl)pyrrolidin-1-yl group, is introduced via a carbon-nitrogen bond into the 7-position of the quinolone skeleton and which is relevant to this invention. This application describes compounds represented by the formulas C and D. However, this application does not contain any description whatsoever concerning a 3-(1-aminocycloalkyl) pyrrolidin-1-yl group, which is relevant to the present invention, as a substituent at the 7-position of the quinolone skeleton shown in formula C. Furthermore, this application does not contain any description whatsoever concerning 3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolone carboxylic acids, which are relevant to the present invention and have the abovementioned group as a substituent.

[In the above formula C, R1 represents a cyclic alkyl group having 3 to 6 carbon atoms, an alkyl group having 1 or 2 carbon atoms, a straight-chain alkenyl group having 2 to 3 carbon atoms, or a branched-chain alkyl group or alkenyl group having 3 to 4 carbon atoms, this alkyl group or cyclic alkyl group may be unsubstituted or the alkyl group or cyclic alkyl group may be substituted by 1 to 3 fluorine atoms or by a phenyl group which is unsubstituted or is substituted by 1 to 3 fluorine atoms or is substituted at the 4-position by a single hydroxyl group, R6 represents a hydrogen atom, a hydroxyl group, an aminocarbonyl group, a bromine atom, a cyano group, an alkyl group having 1 or 2 carbon atoms, or an alkenyl group or alkynyl group having 2 to 4 carbon atoms, and this alkyl group may be unsubstituted or the alkyl group may be substituted by a methyl group or an ethyl group that is unsubstituted or is substituted by 1 to 3 fluorine atoms or one hydroxyl group or amino group. (The definitions of the substituents in the compound shown in formula C are those given in PCT/WO99/14214 and are irrelevant to the definitions of substituents of the present invention even when the same symbols are used.)]
In the above formula, X is represented by formula D:

[In the above formula D, R7 represents an amino group, which is bonded to a carbon that is not adjacent the nitrogen atom of the pyrrolidine ring and may be unsubstituted or substituted by one or two alkyl groups with 1 to 3 carbon atoms, or an aminoalkyl group, which is bonded to a carbon on the pyrrolidine ring and may be unsubstituted or substituted by an alkyl group having 1 to 3 carbon atoms, R9 represents a group selected from among the group comprised of a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group and alkynyl group having 2 to 6 carbon atoms, and fused and spiroalkyl group having 3 to 6 carbon atoms, the alkyl group portions of these groups may be unsubstituted or substituted by 1 to 3 fluorine atoms, and the abovementioned substituents R7 and R9 may be integrated to form a fused or spiro type ring structure with the pyrrolidine ring, with this fused or spirocyclic part being formed from 2 to 5 carbon atoms and 0 or 1 nitrogen atom. (The definitions of the substituents in the compound shown in formula D are those given in PCT/WO99/14214 and are irrelevant to the definitions of substituents of the present invention even when the same symbols are used.)]
Other examples of literature that indicate 6-hydrogen-substituted-quinolone carboxylic acid derivatives, which are relevant to the present invention, include Journal of Medicinal Chemistry, vol. 39, p. 4952 (1996). However, even this literature does not contain any description whatsoever concerning 3-(1-aminocycloalkyl)pyrrolidinyl-substituted-6-hydrogen-substituted-quinolone carboxylic acids, which are the compounds of the present invention.